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Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
Frontiers in Cellular Neuroscience, Volume: 17
Swansea University Authors:
Rhian Evans, Lewis Watkins, Kristen Hawkins, Gabriella Santiago, Constantinos Demetriou, James Neal, Owain Howell
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© 2023 Evans, Watkins, Hawkins, Santiago, Demetriou, Naughton, Dittmer, Rees, Fitzgerald, Morgan, Neal and Howell. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0).
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DOI (Published version): 10.3389/fncel.2023.1094106
Abstract
Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activatio...
| Published in: | Frontiers in Cellular Neuroscience |
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| ISSN: | 1662-5102 |
| Published: |
Frontiers Media SA
2023
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa63788 |
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| Abstract: |
Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination. |
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| Keywords: |
Complement, demyelination, leptomeninges, microglia, inflammation |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This work was supported by funds from the MacDaid Fellowship, Worshipful Livery Company of Wales, the Life Science Research Network Wales, the UK Multiple Sclerosis Society, and the Research Wales Innovation Fund and the BRAIN Unit Infrastructure Award (Grant no: UA05; funded by Welsh Government through Health and Care Research Wales). |